N-acyloxyalkyl substituted derivatives of aminoalkoxydiarylmethanes and salts thereof



Patented Feb. 16, 1954 UNITED STAT ENT OFFICE 2,669,577 N-ACYLOXYALKYL SUBSTITUTED DERIVA- TIVES 0F AMINOA ANES AND SALTS T LKOXYDIARYLMETH- HERE 0F John W. Cusic, Skokie, 111., assignor to G. D. Searle & 00., Chicago, Ill., a. corporation of Illinois No Drawing. Application September 16, 1950, Serial No. 185,319

10 Claims.

wherein Ar and Ar are aromatic radicals, All: is an alkylene radical, R is alkyl, hydrogen or an acyloxyalkyl radical of the formula In the foregoing structural formula, the radi icals Ar and Ar are exemplified by aromatic hydrocarbon groups such as phenyl, tolyl, ethylphenyl, Xylyl, naphthyl, xenyl and the like; by halogenated and alkoxylated aromatic hydrocarbon groups such as chlorophenyl, bromophenyl,

anisyl and veratryl; and by heterocyclic radicals which are aromatic in character, including pyridyl, thienyl, pyrimidyl, thiazolyl and related radicals. Ar and Ar can represent the same or different aromatic radicals.

The alkylene radicals, Alk and X, represent bivalent radicals derived from saturated hydrocarbons by the removal of hydrogen atoms from two different carbon atoms. They therefore include such radicals as ethylene, propylene, trimethylene, tetramethylene, 1,2-butylene, 2,3-butylene, LS-butylene, the amylenes and higher bivalent aliphatic radicals.

The radical R represents hydrogen and lower alkyl radicals containing 1 to 6 carbon atoms which be straight or branched chained, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, secondary amyl, hexyl, and the like. R also represents acyloxyalkyl radicals such as ,s-acetoxyethyl, -acetoxypropyl, fi-propionoxypropyl, ,c-butyroxyisopropyl, ay-diacetoxypropyl, 6 valeroxybutyl, 7 benzoxybutyl, 3 (phenylacetoxy)amyl, and related radicals. The radical R represents lower alkyl radicals of the foregoing type and lower aromatic carbocyclic radicals such as phenyl, tolyl, Xylyl, chlorophenyl, bromophenyl, methoxyphenyl, ethoxyphenyl, and related aromatic monocarbocyclic radicals.

The compounds to which this invention relates are of use as therapeutic agents. They are in general antihistaminic, antiallergic and antispasmodic drugs. Certain of them have local anesthetic properties and some are of value in preventing anaphylaxis. The quaternary ammonium salts are surface active and qualities. The organic bases per so are of value as medicinal agents. These are high-boiling oils in general, and are soluble only in organic solvents.

In practice it is preferable to use these organic bases in the form of salts with non-toxic organic and inorganic acids, or as quaternary ammonium salts with reactive organic halides and esters. Among the acids which I have found of value for salt formation are hydrochloric, hydrobromic, hydriodic, sulfuric, phosphoric, tartaric, ascorbic, sulfamic, citric, acetic, lactic, maleic, malic, succinic, gluconic, benzoic, salicyclic and the like. Reactive esters and halides which are suitable for quaternary salt formation include the alkyl halides such as methyl chloride, methyl iodide, ethyl bromide, propyl bromide, butyl chloride and n-butyl bromide; aralkyl halides such as benzyl bromide, benzyl chloride, naphthylmethyl chloride, phenethyl bromide, anisyl and veratryl chlorides; hydroxyalkyl halides as, for example, ethylene bromohydrin, propylene chlorohydrin, glycerol monochlorohydrin and 6-bromobutano1; esters such as dimethyl sulfate, diethyl sulfate, methyl p-toluenesulfonate, propyl benzenesulfonate and the like. Salts can also be formed by the addition of acidic Xanthine compounds of the type of 8-chlorotheophylline, B-bromotheophylline and related S-haloxanthines. The salts are freebases and are all useful substances; it is understood that in this application and appended claims reference to the bases is also meant to in clude acid addition and quaternary salts thereof.

The basic compounds which comprise my invention can be made by reacting a diarylmethyl haloalkyl ether of the formula have antiseptic wherein Ar and Ar represent aryl nuclei, Alk represents an alkylene chain and X represents a halogen, such as chlorine or bromine, with a primary or secondary amine of the type wherein Z represents a hydroxyalkyl radical and Z represents hydrogen, hydroxyalkyl: or During the reaction the elements of hydrogen halide, HX, are split out and the desired base is obtained. The diarylmethyl haloalkyllether used as a starting material can be obtained by reacting in the presence of alkali a diarylmethyl chloride or bromide with an alkylene halohydrin of the formula HO-Alk-X, where X is chlorine or bromine.

The resulting hydroxy compound is then acylated with an acyl, halide or; anhydride derived from an organic acid oil the formula wherein R has. the meaning designated hereinabove. This reaction is carried out, in an inert solvent which can be neutral or. basic, suchas. a liquid hydrocarbon boiling in the rangeof 504,50 C., as for example in dry benzene, toluene; or xylene, or ina. non-reactive basic solvent such as dry pyridine, quinoline, dimethyl-aniline, diethyle aniline, and related solvents.

The complex organic bases are generally isolated by extraction. with. diluteaqueous. acid whereby the acid. addition salt is iorinedwhich is generally soluble in.- water. and passes into the aqueous phase. The organic'base is isolated from the latter by alkalinization and. extraction. with anorganic. solvent such. as ether, benzene-,, carbon tetrachloride, and the like. If a basic non-reactive solvent is. usedas a reaction medium, the organic bases are preferably isolated from such solvents by evaporation of the solvent, solution of the residue in dilute mineral acid, alkalinization, extraction with a water-immiscible organic solvent and distillation.

My invention is further disclosed bythe fol:- lowing examples which are provided for the: p poses of illustration. and which are in no, to be construed as limiting my invention in spirit or in scope. Relative quantities of materials are '2 given in parts by weight and temperatures are recorded in: degrees centigrade.

Example 1" 285 parts of 8-(methyl-e-hydroxyethylamino) ethyl benzohydryl ether are. dissolvedin 105-parts of dry ether, and 7.8. parts of acetyl chloride are added gradually. After the addition the mixture is allowed to stand for one hour and. then. refluxed gently for one hour. Upon. standing a solid precipitate of pl-(methyl-13-acetoxyethylamino)'- ethyl benzohydryl ether hydrochloride separates. This is removed. and recrystallized from isopropanol diluted with ether. It forms hygroscopic needles which melt at ail-89 C. The base has the formula.

Example 2 By a similar process using 154 parts of phenylacetyl chloride, there is obtained fi-(N-B-phenylacetoxy ethyl-methyl-amino)ethyl benzohydryl ether, which distills at 252-258 C. at 2 mm. pressure. This base forms a non-crystalline tartrate which is readily soluble in water.

The corresponding benzoyl derivative is made in ether, using 145 parts of benzoyl chloride. It forms a crystalline hydrochloride.

Example 3 27- parts of. B-(ethyl-B-hydroxyethylamino)- ethyl benzohyd-ryl ether and 12 parts of acetyl chloride; in 80. parts of dry toluene are refluxed for 15 hours. The solution is cooled and extracted with dilute; hydrochloric acid. The acid extract is made. alkaline and extracted with ether. The ether solution is dried and evaporated and. the: residue of e-(ethyl-fi-acetoxyethylamino) ethyl benzohydryl ether distills at 197-199 C. at 2 mm. pressure. The hydrochloride is prepared by reacting an ether solution with an equivalent of absolute alcoholic hydrogen chloride. A-f-ter recrystallization from ethyl acetate this salt melts at 93-94 C.

Example 4,

427: parts. of B--(methyl-e -hydroxyethylamino) ethyl benzohydryl' ether in 1000 parts of absolute other are added slowly with good: agitation to a solution of 329 parts of B-carbethoxypropionyl chloride in 1100 parts of absolute ether at 0 C. The oily precipitate which forms is. isolated and distilled under reduced pressure. It boils at 242- 24g C. at, 2 mm. pressure and, forms a non-crystalline hydrochloride and. a. non-crystalline citrate, both of which are readily soluble in water, forming 5% solutions which are suitable for medicinal use. The base has. the. formula Example 5 A solution of 20 parts of the. organic base obtained in Example 4 and 5 parts of methyl chloride in 60 parts of methyl ethyl ketoneis heated at 60- C. for 15 hours in a closed vessel. The reaction mixture is chilled and the crystallineprecipitate is. removed and dried. The methochloride thus obtained melts at 123-424 C.

Example 6 5.10. parts. of [3-di-methylaminoethyl benzohydryl ether and 501. parts. of fi-bromoethyl acetate: are heated in 400 parts of methyl ethyl ketone at 75- C. for two, days in a closed vessel. The reaction. mixture is chilled and diluted with anhydrous. ether causing the formation of an oily precipitate of 13- (dimethyl-p acetoxyethylamino).- ethyl benzohydryl ether bromide. This precipitate is removed by decantation, dissolved in a mixture of isopropanol' and ethyl acetate, chilled and dilutedwith anhydrous ether. The oily precipitatewhicir forms soon. crystallizes on standing. The; product so obtained melts at 88-90 C.

I claim:

1. A member selected from the group consisting of, esters. of a dlarylmcthyl N-substituted aminoalkyl ether having th formula and addition salts on the amino group thereof, wherein Ar and Ar are monocycl-icaromatic radicals, All: and X are lower alkylene radicals, R a member selectedfrom the group consistaminoalkyl ether having the formula Cull, R

CH-OAlk-N CoHa X-O-COR wherein Alk and X are lower alkylene radicals, and R and R are lower alkyl radicals.

4. An ester of a benzohydryl N-substituted aminoalkyl ether having the formula wherein R and R are lower alkyl radicals.

5. ,3-(Methyl-p-acetoxyethylamino) ethyl benzohydryl ether, having the formula C H5 C H: CH-OCH2OH2N/ CoHs CHaCHr-O-C O-GH: 6. B (Methyl ,3 phenylacetoxyethylamino) ethyl benzohydryl ether, having the formula 7. An ester of a diarylmethyl N-substituted aminoalkyl ether having the formula wherein Ar and Ar are monocyclic aromatic radicals, All; and X are lower alkylene radicals, R is a lower alkyl radical, and R is a lower carbalkoxyalkyl radical.

'8. An ester of a benzohydryl N-substituted aminoalkyl ether having the formula wherein Alk and X are lower alkylene radicals, R is a lower alkyl radical, and R is a lower carbalkoxyalkyl radical.

9. An ester of a benzohydryl N-substituted aminoalkyl ether having the formula wherein R is a lower alkyl radical and R is a lower carbalkoxyalkyl radical.

10. e (Methyl p carbethoxymethylacetoxyethylamino) ethyl benzohydryl ether, having the formula CuHs /CHa CH-O-CHzCHz-N CaHa CHzCHz-O-C O-OHQCHZ-COO-CZHB JOHN W. CUSIC. References Cited in the file of this patent UNITED STATES PATENTS Name Date Cusic Dec. 5, 1950 Number 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF ESTERS OF A DIARYLMETHYL N-SUBSTITUTED AMINOALKYL ETHER HAVING THE FORMULA 